From Protein Structure to Function with Bioinformatics.pdf

8 3D Motifs 1978.3.1 User-Defined MotifsMethods for matching user-defined 3D motifs are typically demonstrated on a fewmotifs known from the literature. The most commonly used example is the Ser-His-Aspcatalytic triad, first recognized in serine proteases (Blow et al. 1969; Wright et al.1969) and later in other hydrolases such as esterases and lipases. A good test systembecause it has been very well studied and there are many examples in the PDBdatabase of known structures, the catalytic triad has often been used to evaluate theperformance of methods for generating and evaluating 3D motifs. The catalytictriad occurs in different folds, and thus it encompasses cases of both divergent andconvergent evolution (Fig. 8.2).With a serine protease query, geometric hashing using minimal structural information,only alpha-carbon positions (and not their residue types or sequence order),was able to identify not only other serine proteases, but also similar substructuresFig. 8.2 Two serine proteases superimposed at their catalytic triads reveals the close similarity ofresidues in the active sites despite different overall folds. (a) Ribbon diagrams of trypsin (blue/light blue, PDB 1sgt) and proteinase K, a homologue of subtilisin, (red/salmon, PDB 2pkc) showthat the two proteins have different folds with no corresponding secondary structure elements, yettheir catalytic triads (displayed in stick representation) overlap. They are considered to have nocommon ancestor. (b) The side chains of the catalytic triads are shown enlarged to display thesimilar orientations of the catalytic triad residues (1sgt: Asp102, His57, Ser195; and 2pkc: Asp39,His69, Ser224). The similarity of the catalytic triad in these non-homologous structures demonstratesthe ability of 3D motifs to detect similar functions in a pair of proteins where homologybasedmethods will fail. The image was created with UCSF Chimera (Pettersen et al. 2004)(http://www.cgl.ucsf.edu/chimera)